Stent-induced restenosis in the swine coronary artery is inhibited by a platelet-derived growth factor receptor tyrosine kinase inhibitor, TKI963.

Abstract: Activities of vascular smooth muscle cells (SMCs) such as proliferation, migration, and matrix production contribute to restenosis following clinical interventions of angioplasty and stent placement. Because activation of platelet-derived growth factor (PDGF)-receptor tyrosine kinase (PDGFr-TK) influences these processes and promotes restenosis, TKI963, an inhibitor of the PDGFr-TK was discovered, and its efficacy was evaluated in blocking stent-induced restenosis as analyzed by intravascular ultrasound (IVUS). TKI963, a low-molecular-weight compound, inhibited the cell-free PDGFβr-TK with a Ki value of 56 ± 14 n M. TKI963 also inhibited PDGF-dependent events in human aortic SMCs (e.g., in situ PDGFr autophosphorylation, mitogenesis, chemotaxis, and collagen production with median inhibitory concentration values of approximately 300 n M) without affecting the activity of a series of membrane receptor tyrosine kinases and intracellular serine/threonine kinases. In vivo, stent-induced restenosis in the swine coronary artery was reduced by oral administration of TKI963 (1.25, 2.5, and 5 mg/kg BID, for 28 days). Late lumen cross-sectional area (CSA) loss, plaque CSA growth, and plaque volume in the stent determined by IVUS were dose-relatedly decreased (33–62% at 1.25 mg/kg BID to 66–92% at 5 mg/kg BID, depending on the parameter) compared with controls. TKI963 treatment of ≤1 week following stent placement had no effect on the prevention of restenosis. TKI963, a selective, orally bioavailable inhibitor of the PDGFr-TK, dose-relatedly reduced stent-induced restenosis and did so by inhibiting PDGF-dependent activities that occur as late events following stent placement.